Neuroinflammatory conditions are a significant health concern. For example, multiple sclerosis (MS) is an immune-mediated inflammatory disorder of the central nervous system (CNS) characterized by multifocal areas of leukocyte infiltration, demyelination and axonal damage. Typically, demyelination is centered around pericapillary and periveinular accumulation of CD4+ and CD8+ memory T lymphocytes, macrophages and dendritic cells (DCs). These cells arise from migration of peripheral blood (PB) immune cells across the CNS microvascular endothelium.
There are few treatment regimens currently used in MS. Corticosteroids have anti-inflammatory and immunosuppressive effects, which also transiently restores the blood-brain barrier (Noseworthy et al., (2000) Neurology 54(9): 1726-33). They shorten the duration of the relapse and accelerate recovery. Since they are only effective as a short-term treatment, they are most commonly used to treat an acute relapse (Andersson and Goodkin, (1998) J Neurol Sci. 160(1): 16-25; Bansil et al., (1995) Ann Neurol. 37 Suppl 1: S87-101). Further, the responsiveness to corticosteroids declines over time, and extended use may lead to adrenal suppression, cardiovascular collapse and arrhythmias. (C. F. Lacy et al., Drug information handbook 8th Edition, 2001, pp. 549-551).
Interferon (IFN)-β has been used as a therapy for patients with active Relapsing/Remitting Multiple Sclerosis (RRMS) since the 1980's. It is recently being used for secondary progressive patients as well. Recombinant IFN is available in 3 drugs: IFN-β-Ib (Betaseron™) and two IFNβ-Ia preparations (Avonex™ and Rebif™) (Polman and Uitedehaag, supra). These drugs reduce the rate of clinical relapse. However, neutralizing antibodies develop against these drugs rendering them ineffective with time. Also, flu-like symptoms are a prominent side effect early on in the treatment.
Glatiramer acetate (Copaxone™) is a synthetic co-polymer of tyrosine, glutamate, alanine and lysine, thought to mimic myelin basic protein (MBP) and thus, block T cell recognition of MBP (Karin N. et al., (1994) J Exp Med. 180(6): 2227-37). This drug is therefore beneficial in RRMS but not progressive MS. This drug also decreases the rate of relapse and appears to be better tolerated by patients than interferon therapy. Further, treatment with this drug may cause cardiovascular problems such as chest pain, flushing and tachycardia, and respiratory problems such as dyspnea (C. F. Lacy et al., supra).
Another drug that has been approved for the use in RRMS and secondary progressive MS is mitoxantrone. This drug is used to arrest the cell cycle and prevent cellular division, and it is primarily used in the treatment of leukemia (Rolak L. A., (2001) Neurol Clin. 19(1): 107-18). In MS, it reduces relapse rate and increases the length between exacerbations. This drug however has long-term side effects causing cardiac toxicity and chronic myeloid leukemias.
Therefore, there are a few moderately effective treatments for RRMS and secondary progressive MS that have shown to reduce both the frequency of the disease and severity of exacerbations.
Spinal cord injury (SCI) occurs due to traumatic injuries resulting from for example traffic accidents, sport accidents, or falls and drops from heights, and spinal cord compression, or the like. It also occurs due to other disorders, for example, when stroke is accompanied by pyramidal tract transection. Spinal cord injury results in permanent loss of motor, sensory and autonomic functions. Following the initial injury, presumably as part of the inflammatory/immune response to the injury, a series of degenerative processes which promote tissue damage beyond the original site of injury are initiated. After the initial mechanical disruption of nerves and nerve fibers at the time of injury, hemorrhaging is usually observed within 30 minutes at the area of damage and may expand over the next few hours. Within several hours following the injury, immune/inflammatory cells, e.g., neutrophils and macrophages, infiltrate the area and cause further damage to the nerve tissue, i.e., cell-mediated damage. These post-traumatic events are referred to as “secondary injury” (or “secondary spinal cord injury”). Therefore, a significant aspect of the tissue damage and functional loss may be preventable as it is the result of secondary events triggered by the trauma. It is important to treat as promptly as possible when the spinal cord is damaged, in order to promote recovery from or to prevent progress, of neurologic function deficit. It would be advantageous to prevent further damage to the spinal cord and surrounding tissue following a spinal cord injury by treatment as soon as possible after the initial trauma to prevent secondary injury effects.
Currently, the conventional treatment for reducing or minimizing the damage resulting from secondary injury is intravenous injection of the glucocorticoid, methylprednisolone (Bracken et al., JAMA, 277(20): 1597-1604 (1997)). Unfortunately, prolonged administration of glucocorticoids has adverse systemic side effects, e.g., increased incidence of sepsis and pneumonia, and a limited therapeutic window. Furthermore, recent studies have raised doubts about the beneficial effects of high doses methylprednisolone after SCI (Schröter et al., Neuroscience 2009 161(3): 753-63. Epub 2009 Apr. 11).
There is therefore a continued need for improved materials and methods for the treatment of conditions/diseases associated with neuroinflammation, such as MS and SCI.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.